The observation that benzene is metabolized to a series of hydroxylated compounds, phenol, catechol and quinol, and causes bone marrow depression is well documented. However, little data are available to confirm or refute a relationship between the two events. The objectives of this proposal are to learn whether hepatic and/or extrahepatic metabolism are responsible for benzene toxicity and to examine the role of benzene metabolites in the expression of the toxicity. If a hepatic metabolite of benzene is responsible for benzenetoxicity, it should be possible to mimic the toxicity by administering benzene's metabolites. The degree of toxicity will be quantified as the percent inhibition of 59Fe uptake into circulating erythrocytes. Failure of any of the metabolites to duplicate the toxicity would indicate that benzene itself or a reactive metabolite formed within the target organ is responsible for the toxicity. Analytical procedures will also be developed, using gas chromatography-mass spectrometry (GC-MS) and stable isotope dilution, to analyze the urinary metabolites resulting from toxic and nontoxic doses of benzene. This technique will be used to determine if the metabolite pattern is altered due to the depletion of endogenous cofactors required to detoxify benzene.